Dendritic and somatodendritic voltage-gated potassium or Kv channels are fundamental components of neuronal signaling. This proposal is aimed at determining the fundamental mechanisms that determine neuronal function through dynamic modulation of intrinsic excitability. We specifically focus on regulation of the abundance, distribution and function of the somatodendritic delayed rectifier Kv2.1 channel, and the dendritic A-type Kv4.2 channel. We have exciting new data that both localization and function of these important Kv channels are dynamically modulated by excitatory neurotransmitter stimulation, and by hypoxia/ischemia. This modulation is via posttranslational effects on the channel proteins, by changes in phosphorylation state (Kv2.1, Kv4.2) and interaction with auxiliary subunits (Kv4.2). Moreover, the dynamic changes in Kv2.1 and Kv4.2 correlate with significant changes in neuronal electrical activity. This proposal is aimed at determining the precise mechanism responsible for the dynamic changes in Kv2.1 localization and function. The proposed project employs state-of-the art mass spectrometric approaches to identify phosphorylation sites on the channel proteins, followed by experiments to directly address the role of such sites in regulating Kv2.1 and Kv4.2 localization and function in both heterologous cells and neurons. The project also entails a comprehensive analysis of the roles of auxiliary subunits of Kv4.2 channels in the dynamic regulation of Kv4.2 localization and function by synaptic activity. Finally, we will directly intervene in the expression and modulation of these channels and determine effects on electrical activity of neurons in culture and in brain slices. These studies will yield important insights into the reciprocal physiological regulation of Kv2.1, a regulator of homeostatic plasticity, and Kv4.2, a determinant of activity-dependent potentiation.